Piperidine derivatives



Patented Aug. 17, 1954 PIPERIDINE DERIVATIVES Jacob Finkelstein, East Paterson, and John Lee, Essex Fells, N. J., assignors to Hofimann-La Roche Inc., Nutley, N J., a corporation of New Jersey No Drawing. Application July 15, 1950,

, Serial No. 174,116

This invention relates to new chemical compounds which can be described broadly as piperidine derivatives. More specifically, the compound of the invention can be described as dialkylaminophenethyl-piperidine bases and, their salts. The piperidine bases and their salts are useful in the field of therapeutics, and are especially of interest in the field of trichorr onal and amoebic infections. g

, More particularly, the piperidinebases of the, invention are those of the class consisting of 1- alkyl -2 (dialkylaminophenethyl) piperidines and l-alkyl-w (dialkylaminophenethyl) r-piperidines; that is, compounds which can be considered as, structurally derived frompiperidine by substitution of an alkyl radical in the l-position and of a dialkylaminophenethyl radical in piperidine, l-methy1-2-(B-diethylaminophenethyl) -piperidine and 1-methyl-2-(Z-diethylaminophenethyD-piperidine. The compounds of the invention can be represented by the following general Formulae I and II, wherein R R and R each represents an alkyl group:

\N oreom R:

Il -N n 0112011: R3

The salts of the invention embrace the acid 14 Claims. (Cl. 260-293) process comprising reacting an alkyl halide quaternary salt of a methyl-substituted pyridine (e. g. a-picoline methiodide or v-picoline nhexyl bromide) with anaminobenzaldehyde to form a 1-alkyl-2(or 4) -aminostyryl-pyridinium salt, and catalytically reducing the latter to form an acid addition salt of a l-alkyl-2(or 4) -aminophenethyl-piperidine. The free 1-alkyl-2(or\ 4)- aminophenethyl-piperidine base can be liberated from the latter salt by alkalinization, and can then be converted to any desired acid addition salt or quaternary salt by treatment with the appropriate acid or organic quaternizing agent, respectively. If the amino group in the benzaldehyde used as starting material is not already alkylated, alkyl groups can be introduced into the condensation product, i. e. into the aminophenethyl-piperidine base, by reacting the base with appropriate alkylating agents.

The invention is further disclosed in the following examples, which are illustrative but not limitative thereof:

EXAMPLE 1 1-methyl-2-4-dimethylaminophenethyl) .p'iperz'dine 9.3 g. of a-picoline was mixed with 14.2 g. of methyl iodide and allowed to react spontaneously. The resulting white solid, 1,2-dimethylpyridinium iodide (a-picoline methiodide), was taken up in 270 cc. of ethanol, and to thereaction mixture were added 15 g. of p-dimethylaminobenzaldehyde and 4 cc. of piperidine. The reaction mixture was refluxed for about 5 hours. At the end of this time, it was cooled and the precipitate was filtered off and recrystallized from methanol. The resulting material was 1- methyl 2 (4 dimethylaminostyryl) pyridinium iodide, M. P. approximately 260 C. with decomposition.

9L6 g. of the latter compound was suspended in 150 cc. of per cent ethanol and hydrogenatedat 50-60 C. under lbs. hydrogen pressure in the presence of 200 mg. of platinum dioxide. The reaction mixture was filtered to separate the catalyst, concentrated and cooled. The crystalline precipitate was separated and recrystallized from alcohol to yield a product having a melting point of approximately 182- 183 C., which was 1-methyl-2-(4-dimethylaminophenethyl) -piperidine monohydriodide.

The free base was obtained by adding to a suspension of 100 g. of the above hydriodicle in cc. of water suificient strong sodium hydroxide to make the solution alkaline. The resulting oil was taken up in ether, the ethereal extract was dried over potassium hydroxide and concentrated. The residue was submitted to fractionation under reduced pressure, yielding a colorless oil, B. P. approximately l57-158 C. at 1 mm. Hg. This product was l-methyl-Z-( l-dimethylaminophenethyl) piperidine.

To 3 g. of the above oil, dissolved in dry ether,

alcoholic hydrogen chloride was added. The

mixture was cooled and the crystalline precipitate filtered off and recrystallized from an alcoholether mixture, and dried in vacuo at 100 C. over phosphorus pentoxide; M. 'P. approximately 176-178 C. with decomposition. This material was 1-methyl-2- (4-dimethylaminophenethyl) piperidine dihydrochloride.

3 g. of the free base 1-methyl-2-(4-dimethylaminophenethyl) -piperidine was reacted with an excess of an acetone solution of methyl bromide. The reaction mixture was cooled, the solid material was filtered ofi, and washed with acetone. The resulting product was recrystallized and dried. It was 1.1 dimethyl 2 (4 dimethylaminophenethyl)-piperidinium bromide, M. P. approximately 234-236 C.

g. of 1-methyl-2-( l-dimethylaminophenethyl) -piperidine and g. of ethyl iodide were heated on the steam bath for 3 hours. The resulting crystalline product was recrystallized from alcohol. It was l-methyl-l-ethy1-2-(l-dimethylaminophenethyl) piperidinium iodide, M. P. approximately 202-204 C. with decomposition.

2.6 g. of l-methyl-Z-( l-dimethylaminophenethyl) -piperidine was mixed with 1.3 g. of benzyl chloride and 50 cc. of dry xylene. The reaction mixture was refluxed for 4 hours, and then concentrated in vacuo. The residue was triturated with ether and filtered. The precipitate was recrystallized from alcohol to give a product melting at approximately 21l-212 C., which was 1-methyl-1-benzyl-2-(4-dimethy1- aminophenethyl) -piperidinium chloride.

EXAMPLE. 2 Y

1 meth'yl 2 (4 diethylaminophenethybpiperidz'ne 46.5 g. of u-picoline was allowed to react with 71 g. of methyl iodide. To the reaction mixture were added 500 cc. of ethanol, 90 g. of p-diethylaminobenzaldehyde and 10 cc. of piperidine. The reaction mixture was refluxed for 6 hours, cooled and filtered. The crystalline product, l-methyl- 2 (4 diethylaminostyryl) pyridinium iodide, after drying at 100 C. in vacuo, melted at approximately 230- 232 C.

To 100 g. of 1-methyl-2-(4-diethylaminostyryl) -pyridinium iodide, prepared as described above, were added 1400 cc. of 95 per cent ethyl alcohol, and 300 mg. of platinum dioxide. reaction mixture was maintained at 50 C. and hydrogenated under a hydrogen pressure of 150 lbs. After completion of the hydrogenation, the reaction mixture was cooled and filtered, and to the filtrate was added 250 cc. of 1 N NaOH. The reaction mixture was concentrated on the steam bath, and the oil which separated was extracted with chloroform. The chloroform extract was washed with water, dried and concentrated. The residual oil was fractionated, in vacuo to give a product having a boiling point of approximately 175 C. at 2 mm. Hg. This product was l-methyl- 2- 4-diethylaminophenethyl) -piperidine.

1 methyl 2 (4 diethylaminophenethyl) The base.

pared by heating 21 g. of the free base with 30 g.

of ethyl iodide in- 50 cc. of alcohol at 125 C. for approximately 5 hours. The solution was cooled and allowed to stand and the resulting crystalline product, 1-methyl-2-(d-diethylaminophenethyl) -piperidine di-ethiodide, was filtered off; M. P. approximately 202-206 C.

EXAMPLE 3 1 -ethyl-2- (4-diethylaminophenethyl) -piperidine 100 g. of ethyl iodide was mixed with 62 g. of a-picoline. Slight warming started the reaction which then continued spontaneously until the entire reaction mixture was solid. To 40 g. of' 1-ethyl-Z-methyl-pyridinium iodide, thus prepared, were added 100 cc. of per cent ethanol, 28.4 g. of p-diethylaminobenzaldehyde and 2 cc. of piperidine. The reaction mixture was refluxed for 6 hours. Then it was cooled to room temperature, the resulting crystals were filtered off, recrystallized from alcohol, and dried. The product a was 1 ethyl 2 (4 diethylaminostyryl)-' pyridinium iodide, M. P. approximately 195- 196 C.

35.5 g. of l-ethy1-2-( l-diethylaminostyryl)- pyridinium iodide was suspended in 800 cc. of 95 per cent alcohol, and reduced, at 50 C. under lbs. hydrogen pressure in the presence of platinum dioxide, as described above. When the hydrogenation was completed, the reaction mixture was cooled and the catalyst was filtered off, and to the filtrate was added 100 cc. of 1 N NaOI-I. Then the alcohol was distilled ofi, the residue was extracted with ether and the ethereal extract was dried. Upon concentration of the extract,

an oil was obtained which was fractioned to obtain a product, 1-ethyl-2-(4-diethylaminophenethyl) -piperidine, having a B. P. of approximately 184-186 C. at 4 mm. Hg.

The dihydrochloride of the above base was prepared by reacting 7.0 g. of the base with 48.5 cc. of l N I-ICl.

The mono-ethiodide quaternary salt was prepared by refiuxin 28 g. of the above base with 50 g. of ethyl iodide in 200 cc. of methyl ethyl ketone for approximately 12 hours. After recrystallization from alcohol, the product, 1,1-diethyl 2 (4 diethylaminophenethyl) piperidinium iodide, melted at approximately 194- EXAMPLE 4 1 -methyl-2-(3-aminophnethyl) -piperidine To 235 g. of oc-DlCOlillE methiodide, prepared as described in Example 1, were added 15.1 g. of m-nitrobenzaldehyde, cc. of ethanol and 3 cc. of piperidine. The reaction mixture was refluxed for about 6 hours, cooled, and the crystalline material filtered off, washed with alcohol and dried on a steam bath. After recrystallization from Water the product melted at approximately 248- oi the free 2- (4-diethylaminostyryl) pyridinium 74. g. of theabove product was hissolvedfin 800cc; of"95 per cent alcohol and reduced with hydrogen in the presence of platinumdioxide at 50 C. and undera hydrogen pressureof 2 lbsl, as described in Example 1. The catalyst was filtered ofi and tothe filtrate was added 220 cc. of 1 N NaOH. The reaction mixture was concentrated by removing the solvent, and there sulting oil wastakennp in ether. The ether solution was washed with water and dried over potassium carbonate and then; distilled under reduced pressure to give a product having a B. P. of approximately '138- 144 C., which was 1- methyl-2- (3-aminophenethyl) -piperidine.

1 .A monohydrochloride of the above basewas prepared by reacting21 g. of the free base with approximately 96 cc. oflN HCl. i a

1 Q methyl 2 (3 diethylaminophenethybpiperid ine peridine (Example 4) was mixed with 30 g. of

triethyl phosphate and refluxed for two hours. Then the reactionmixture was cooled and 115 cc.

of 30 per centNaOHwasaddedfand the reaction mixture was agia idrefiuxed forr l 'jhours. At the ndof this time, the reaction mixture was cooled, poured into water, and the aqueous mixture was extracted withetheia. Theether extract was washed with water, driedandconcentrated. The residue was fractionated under reducedfpres sure. The fraction boiling at j.'approximately 174-180 C. at 3 mm. Hg was l-methyl-2-(3 diethylaminophenethyll-piperidine.

he i roc lor d o t e lat om ou wasprepared by reacting approximately g. base with approximately 73. cc. of lgNHCL l XA P EBQ hours. After, standing for anIho ur, jthereaction mixture, wasfextracted alternately with seyeral portions of l ether and petroleum ether. The ex.- tracts were discarded and the; insoluble joil was allowed to: stand at 0 C. for about lfi houis. to crystallize. The crystals were filtered .ofi, and washed with ether and petroleum ether. The compound ,was" l,-n hexyl-'2 methylpyridinium bromide. f 1 To 25.8 g. of the latter, quaternary salt were added 17.7 g. of p diethylarninobenzaldehyde, 100 cc. of alcohol and 5cc.fof :p'iperidine. The reaction mixture wasreliluxed on asteam bath for 13 hours. Then the reaction mixture was concentrated and the product was filtered off and recrystallized from isopropyl alcohol. It was l-n-hexylbromide, M. P. approximately 216-217 C. V l

110 g. of the latterproduct in-1000 cc. of 95 per cent alcohol was hydrogenated at 50? C. under 200 lbs. hydrogen pressure in; the presence of platinum dioxide. The reaction, mixture .was ,fil tered, alkalinized and worked up as ,describedin Examples 2 to 4, andyielded. a, product having-la B. P. of approximately 1993-201". Chat 1 mm. Hg, which 1 was l-n-hexy-l-Zw(4-diethylaminophenethyl) -piperidine.

of l-methyl-2 (3-aminophenethyl) 131- temperature for 1% hours. Then it was cooled, and 130.5 g. of di-n-hexyl-aniline was added while keeping the temperature at 5-15 C. The reac tion mixture was heated at (50-70 C. for 2 hours, then poured into a mixture of ice and water. Two layers, an aqueous layer and an oily layer, were formed. Theoil layer was separated,

taken up in benzene, and the benzene extract was washed with alkali and then with water. The solvent was removed, and the residual oil fractioned under reduced pressure. The fraction boiling at approximately 205207 C. under 2 mm. Hg was p-di-n-hexylaminobenzaldehyde.

,A mixture of 36.6 g. of l-n-hexyl-2-methylpyridinium bromide (Example 6), 41 g. of p-di-nhexylaminobenzaldehyde, 40 g. of ethanol and 5 cc. of piperidine was refluxed for 2 hours. The crystalline product was filtered off and recrystallized from isopropanol; M. P. approximately 224 227 C. It was 1-n-hexyl-2- (a-di-n-hexylaminostyryl) -pyridinium bromide.

44 g. of 1-n-hexyl-2-(4-di-n-hexylaminostyryD-pyridinium bromidewas reduced in 500 cc. of 95 per cent alcohol at 50 C. and under 200 lbs. hydrogen pressure, in the presence of platinum' dioxide. The free base was isolated in the manner described in Examples 2 to 4. The prodnot, having a B. P. of approximately 252-256 C. at 1 mm. Hg, was l-n-hexyl-Z-(4-di-n-hexylaminophenethyl) -piperidine.

The dihydrochloride was prepared by reactin g. of the free base with 65 cc. of IN 1101.

EXAMPLE 8 r e r 1 -ethyl-2- (4-di-n-hexylaminophenethyll -piperi- .dine

r A mixture of 17.8 g. of 1-ethyl-2-methyl-pyridinium iodide (Example 3), 29.7 g. of p-di-n-hexylaminobenzaldehyde (Example '7), cc. of alcohol and 5 cc; of piperidine was refluxed for 6 /2 hours. The reaction mixture was cooled and the base with 50 cc. of 1 N HCl.

EXAMPLE 9 1 -methyZ-4- (4-dimethylaminophenethyl) -p'iperidine 47 g. 0t 1,4-dimethyl-pyridinium iodide ("ypicoline methiodide), prepared by the spontaneous reaction between equivalent amounts of ypicoline and methyl iodide, was'mixed with g.

aescnsa.

methylaminophenethyl)-piperidine, had a B. P.

of approximately 150-156 C. at approximately 1 Him. Hg. g. of the latter compound was reacted with an excess of an acetone solution of methyl bromide. The resulting product, 1,1-dimethyl-4-(4- dimethylaminophenethyl) -piperidinium bromide, had a M. P. of approximately 24.5-251 C.

The benzyl bromide quaternary salt Was prepared by mixing 5 g. of the free base with an excess of benzyl bromide in benzene. The product was l-methyl-l-benzyll-(4-dimethylaminophenethyl) piperidinium bromide.

EXAMPLE I-methyl 4 (4-diethylaminophenethyl) -piperidine 93 g. of 7-1310011116 was reacted with 142 g. of methyl iodide. To the -picoline methiodide so formed were added 600 cc. of methanol, 250 g. of p-diethylaminobenzaldehyde, and 20 cc. of piperidine. The reaction mixture was refluxed for 5 hours. The product was l-methyl--( l-diethylaminostyryl) -pyridinium iodide, m. p. approximately 217-220 C.

253 g. of the latter product in 1100 cc. of 95 per cent alcohol was subjected to catalytic hydrogenation at 50 C. under 200 lbs. hydrogen pressure in the presence of 300 mg. of platinum dioxide. The product was isolated as described in Examples 2 to 4, by alkalinization and extraction of the reaction mixture. The product, 1- methyl 4 (4 diethylaminophenethyl) -piperidine, had a B. P. of approximately 165-170 C. at 1 mm. Hg.

The'dihydrochloride was prepared by treating approximately g. of the free base with approximately 110 cc. of 1 N I-ICl.

By reacting the free base with an excess of an acetone solution of methyl bromide, the quaternary salt 1,1-dimethyl-4-( l-diethylaminophenethyl) -piperidinium bromide, M. P. approximately 232235 C., was prepared.

EXAMPLE 11 I 1 ethyl-4- (4-diethylaminophenethyl) -piperidine 93 g. of y-picOliIlG was mixed with 156 g. of ethyl iodide in benzene and refluxed. After 2 hours, the reaction was stopped and the reaction mixture was cooled. The precipitate of the product, l-ethyl-i-methyl-pyridinium iodide, was filtered off.

125 g. of the latter product, 87 g. of p-diethyl aminobenzaldehyde, 300 cc. of ethanol and 10 cc. of piperidine were refluxed for 5 hours. The product, l-ethylll-diethylaminostyryl) -pyridinium iodide, had a M. P. of approximately 200-205 C.

80 g. of the latter product in 700 cc. of 95 per cent alcohol was reduced at 50 C. and 200 lbs. hydrogen pressure in the presence of platinum dioxide. The product, 1-ethy1-4-(4-diethylaminophenethyl)-piperidine, was obtained by alkalinization of the reaction mixture, extraction with benzene, and isolation of the product under reduced pressure. It had a B. P. of approximately 163-l65 C. at 1 mm. Hg. g The dihydrochloride was prepared by reacting 10 g. of the free base with approximately 70 cc. ofl N HCl. By reacting the free base with an acetone solution of methyl bromide, the di-quaternary salt, l-ethyl 4 (4 diethylaminophenethyl) -piperidine di-methobromide, M. P. approximately 204-205 C. after recrystallization from isopropanol, was obtained.

EXAMPLE 12 1 -ethyZ-4- (4-di-n-heacylaminophenethyl) piperidine 12.5 g. of 1-ethyl-4-methyl-pyridinium iodide (Example 11), 14.5 g. of p-di-n-hexylaminobenzaldehyde (Example 7), 15 cc. of alcohol, and 2 cc. of piperidine were refluxed for 16 hours. The product, l-ethyll-(4-di-n-hexylaminostyryD-pyridinium iodide, after recrystallization from isopropanol, melted at approximately 150-154 C.

27.5 g. of the latter product in 210 cc. of 95 per cent ethanol was reduced by catalytic hydrogenation in the presence of platinum oxide at C. under 200 lbs. hydrogen pressure. The reaction mixture was worked up in the manner described in Examples 2 to 4. The product, 1- ethyl-4-(4 di-n-hexylaminophenethyl) piperidine, had a B. P. of approximately 227-231 C. at 0.5 mm. Hg.

The corresponding dihydrochloride was pre pared by reacting 15.6 g. of the free base with 78 cc. of 1 N HCl.

EXAMPLE 13 1 -n-hea:yl-4- 4 -di-n-hexylaminophenethyl) piperidine 1-n-hexyl-4-methyl-pyridinium bromide ('ypicoline n-hexyl bromide) was prepared by heating 93 g. of 'y-picoline with 139 g. of n-hexyl bromide at 135-140 C. for 24 hours. After cooling, the unreacted starting materials were removed from the crystalline product by extraction with dry ether.

16 g. of l-n-hexyl--methyl pyridinium bromide, 18 g. of p-di-n-hexyl-aminobenzaldehyde, 10 cc. of ethanol, and 1 cc. of piperidine were refluxed for 12 hours. The product obtained was l-n-hexyl 4 (4-di-n-hexylaminostyryl)-pyridinium bromide.

15 g. of the latter product in 100 cc. of per cent alcohol was subjected to catalytic hydrogenation at 40 C. under 200 lbs. hydrogen pressure in the presence of platinum dioxide. The reduction product isolated was 1-n-hexyl-4-(4- di-n-hexylaminophenethyl) -piperidine.

The dihydrochloride was prepared by reacting 15 g. of the base with approximately 65 cc. of 1 N 01.

EXAMPLE 14 1 -n-hexyZ-4- (4-diethylaminophenethyl) piperidine 129 g. of 1-n-hexyl-l-methyl-pyridinium bromide (Example 13), 89 g. of p-diethylamino- 1. A compound selected from the group consisting of 1-alkyl-2-dialkylaminophenethyl-piperidines, l-alkyl-4-dialkylaminophenethyl-piperidines, and salts of these piperidines; each of the alkyl groups in said compound being a lower alkyl group.

2. A 1-alky1-2-(4-dialkylaminophenethyl) -piperidine, each of the alkyl groups therein being a lower alkyl group.

3. A salt of a compound according to claim 2.

4. A 1-alky1-4-(4-dialkylaminophenethyl) -piperidine, each of the alkyl groups therein being a lower alkyl group. i

5. A salt of a compound according to claim 4.

6. 1 methyl-2-(4-dimethylaminophenethyl)- piperidine.

7. 1 n hexyl-4-(4-diethylaminophenethyl)- piperidine.

8. 1 methyl 2 (4-diethylaminophenethyl) piperidine.

9. A salt of the compound of claim 8.

10. A salt of the compound of claim 8 which is an acid addition salt.

piperidine dihydrochloride.

10 12. 1 ethyl-2-(4-diethylaminophenethyl)-piperidine.

13. A compound of the formula CHzCH2 (C2H5)3-2X C R1 wherein R and R are lower alkyl radicals having less than three carbon atoms per radical and X is the anion of a non-toxic acid.

14. 1 ethyl 2 (4-diethylaminophenethyl)- piperidine di-ethiodide.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,355,659 Lee et al. Aug. 15, 1944 FOREIGN PATENTS Number Country Date 595,631 Great Britain Dec. 11, 1947 OTHER REFERENCES Phillips, J. Org. Chem, vol. 12, pp. 333-41 (1947), abstracted: Chem. Abst. 41, 4489 (1947).

Phillips, J. Org.'Chem., vol. 14, pp. 302-5 (1949), abstracted: Chem. Abst. 43. 7483 (1949).

Phillips, J. Am. Chem. Soc., vol. 72, pp. 1850-2 (1950), abstracted: Chem. Abst. 44, pp. 4964- 4965 (1950). 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1-ALKYL-2-DIALKYLAMINOPHENETHYL-PIPERIDINES, 1-ALKYL-4-DIALKYLAMINOPHENETHYL-PIPERIDINES, AND SALTS OF THESE PIPERIDINES; EACH OF THE ALKYL GROUPS IN SAID COMPOUND BEING A LOWER ALKYL GROUP.
 13. A COMPOUND OF THE FORMULA 